Preoperative clinicopathologic characteristics of 53 NETLM patients who underwent debulking are displayed in Table 1. The majority had a well differentiated, metastatic SBNET (n = 34) or a PNET (n = 15) with grade 1 or 2 disease. One patient had a well-differentiated grade 3 NET and was one of two patients with unknown etiology of primary tumor. The remaining two patients had either a gastric or lung NET. The median age at time of operation was 57 years. 43% of the patient cohort had symptomatic disease, of which 40% had carcinoid syndrome. Over 95% of patients had bilobar liver metastases, and 23% of patients had extrahepatic disease (EHD), with common sites including the peritoneum (diaphragm, omentum and pelvis) or bone. Preoperative systemic therapy with SSA, CAPTEM and/or PRRT had been given in 79%, 11%, and 7.5% of patients, respectively.
Table 1. “Comparison of NET patients preoperative clinicopathologic characteristics”
|
All
|
SBNET
|
PNET
|
p
|
Median age (yrs; range)
|
57 (49-60)
|
57 (49.5-62.3)
|
57 (48-60)
|
0.68
|
Sex
|
|
|
|
|
Male
|
29/53
|
19/34
|
7/15
|
0.76
|
Female
|
24/53
|
15/34
|
8/15
|
|
Race/Ethnicity
White
Black
Hispanic
|
38/48
8/48
2/48
|
23/32
8/32
1/32
|
12/13
0/13
1/13
|
0.13
|
Primary tumor location
Unknown
Stomach
Lung
Head of pancreas
Tail/body of pancreas
SB
|
2
1
1
3
12
34
|
--
--
--
--
--
34
|
--
--
--
3
12
--
|
|
Symptomatic disease
|
25/53
|
21/34
|
3/15
|
0.01
|
Carcinoid syndrome
|
21/52
|
19/34
|
1/14
|
0.03
|
Tumor grade
G1
G2
G3
|
29/52
22/52
1/52
|
25/33
8/33
0/33
|
4/15
11/15
0/15
|
0.003
|
Chromogranin (CgA)
|
200.5 (93.5-771)
|
225.5 (125-621)
|
68 (51-113)
|
0.01
|
Elevated CgA
|
31/42
|
24/25
|
4/11
|
0.006
|
Serotonin
|
894 (185-1818)
|
1140 (566-1955)
|
176 and 256
|
0.16
|
Elevated serotonin or 5-HIAA
|
23/26
|
21/23
|
2/3
|
--
|
AST
|
23 (19-27.8)
|
22 (19-27)
|
23 (20-25.5)
|
0.42
|
ALT
|
22 (16.8-33)
|
19 (15-31)
|
23 (18.5-32.5)
|
0.26
|
Total Bilirubin
|
0.5 (0.3-0.8)
|
0.5 (0.3-0.9)
|
0.5 (0.4 – 0.8)
|
0.88
|
INR
|
1 (1-1)
|
1 (1-1.1)
|
1 (1-1)
|
0.48
|
Bilateral liver mets
|
51/53
|
32/34
|
15/15
|
1.00
|
Lymphadenopathy
|
35/53
|
24/34
|
8/15
|
0.33
|
Extrahepatic disease
|
12/53
|
8/34
|
4/15
|
1.00
|
Preop systemic therapy
Somatostatin analogue
Chemo (CAPTEM)
PRRT
|
43/53
42/53
6/53
4/53
|
28/34
28/34
0/34
2/34
|
14/15
13/15
6/15
2/15
|
0.41
1.00
0.004
0.58
|
Intraoperative characteristics are reported in Table 2. A total of 1069 hepatic lesions were debulked collectively with PSR (45%) and MWA (55%). Stratified by number of lesions, 21% (n = 11) had up to 5 lesions, 23% (n = 12) had 6–15, 28% (n = 15) had 16–25, and 28% (n = 15) had > 25 lesions debulked. The highest number of lesions debulked in one patient was fifty-six. The median number of lesions targeted was 17 overall. All patients, except for two, had > 90% tumor debulking at the time of operation. Over 70% of patients had synchronous resection of the primary tumor as their first operation, which they had on average 6.5 months after initial diagnosis. The average estimated blood loss (EBL) was 300 ml for all cases, 13% of which required at least 1 intraoperative transfusion of packed red blood cells.
Table 2. “Operative characteristics for NETLM patients by tumor type”
|
All
|
SBNET
|
PNET
|
p
|
Time to 1st surgery (months)
|
6.5 (3.0-13.9) (n=38)
|
5.1 (2.8-13.5) (n=26)
|
11.9 (9.9-16.3) (n=10)
|
0.07
|
Primary tumor resection
|
38/52
|
28/34
|
9/15
|
0.15
|
Type of liver debulking
Partial lobectomy
Wedge/enucleation
MWA
Superficial ablation
Formal resection
|
60 total in 38/53
417 total in 48/53
438 total in 47/53
152 total in 6/53
2 total in 3/53
|
36 total in 23/34
294 total in 32/34
244 total in 29/34
52 total in 2/34
2 total in 2/34
|
26 total in 14/15
90 total in 13/15
175 total in 14/15
100 total in 4/15
0/15
|
0.03
0.51
0.03
0.05
0.36
|
Median # of lesions debulked
Total # of lesions debulked
|
17.5 (7-29)
1069
|
16.5 (6-25.8)
632
|
22 (15-38.5)
402
|
0.10
|
Sites of extrahepatic mets
Intraperitoneal (diaphragm,
pelvis, omentum)
Bone
|
10/12
2/12
|
7/8
1/8
|
3/4
1/4
|
1.00
1.00
|
EBL
|
300 (n=52)
(150-500)
|
225
(100-388)
|
500
(250-825)
|
0.007
|
Intraoperative Transfusion
|
7/53
|
2/34
|
5/15
|
0.02
|
With respect to liver function, a surge in liver enzymes measured on post-operative day (POD) 1 was proportional to the numbers of debulked lesions (Fig. 2A, B, C). For patients with 1–15 lesions targeted, the median POD 1 AST and ALT values were 681 and 596 IU/L, respectively, compared to 1396 and 1149 IU/L, respectively, for patients with greater than 15 lesions (Fig. 2A; p = 0.01, p = 0.01). The degree of transaminitis linearly correlated with increasing numbers of hepatic lesions debulked (Fig. 2C; p < 0.0001, p < 0.0001) but this effect typically resolved by POD 5. Synthetic liver function, assessed by changes in post-operative INR, did not differ significantly among patients and did not have a linear correlation with increasing number of lesions (Fig. 2C; p = 0.151). Hypophosphatemia, a common post-operative finding after liver resection, was noted to be most prominent on POD 2, but the degree did not differ among the various numbers of lesions debulked (Fig. 2C).
The median length of inpatient stay after debulking was 7 days (Table 3). Thrombocytopenia (platelets < 150 x 109/L) was the most common complication occurring in over 75% of patients and most cases were transient. Two patients developed heparin-induced thrombocytopenia (HIT) and were excluded from further analyses. The severity of thrombocytopenia was proportionate to the number of lesions debulked (Fig. 2C; p = 0.003) with median POD2 platelet values 157 x 109/L for 1–15 lesions vs. 109 x 109/L for > 15 lesions (Fig. 2A; p = 0.04). However, the incidence of thrombocytopenia did not significantly differ between groups.
Table 3. “Morbidity and Mortality for patients per NET type and number of lesions debulked”. LOS = length of stay; EBL = intraoperative estimated blood loss
|
ALL
|
NET Type
|
No. of lesions debulked
|
SBNET
|
PNET
|
p
|
1-5
|
6-15
|
16-25
|
>25
|
p
|
Total complications
Any
GI
Readmission
Bile leak
PVT
HIT
Thrombocytopenia
Hemorrhage or Anemia
Infection
Need for re-exploration
|
1 (1-2)
45/53
4/53
4/53
4/53
1/53
2/53
41/53
19/53
8/53
2/53
|
1 (1-2)
27/34
2/34
0/34
2/34
0/34
1/34
25/34
9/34
1/34
2/34
|
2 (1-3)
10/14
2/15
2/15
1/15
0/15
0/15
12/15
9/15
6/15
0/15
|
0.006
0.41
0.58
0.08
1.00
1.00
1.00
0.73
0.05
0.002
1.00
|
1 (0.5-1.5)
8/11
1/11
1/11
1/11
0/11
0/11
7/11
2/11
0/11
0/11
|
1 (1-3)
11/12
2/12
1/12
2/12
1/12
1/12
9/12
5/12
3/12
1/12
|
1 (0.5-2)
11/15
0/15
0/15
1/15
0/15
0/15
11/15
6/15
1/15
0/15
|
2 (1-2)
15/15
1/15
2/15
0/15
0/15
1/15
14/15
6/15
4/15
1/15
|
0.30
0.08
0.43
0.60
0.43
0.43
0.84
0.30
0.60
0.16
0.84
|
Clavien-Dindo class
None
I
II
III
IV
|
7/53
25/53
14/53
6/53
1/53
|
7/34
18/34
7/34
1/34
1/34
|
0/15
5/15
7/15
3/15
0/15
|
0.06
|
3/11
6/11
1/11
1/11
0/11
|
1/12
5/12
4/12
1/12
1/12
|
3/15
6/15
3/15
3/15
0/15
|
0/15
8/15
6/15
1/15
0/15
|
0.69
|
Intraop transfusion
|
7/53
|
2/34
|
5/15
|
0.02
|
1/11
|
3/12
|
0/15
|
3/15
|
0.16
|
Post op transfusion
|
17/53
|
9/34
|
8/15
|
0.10
|
1/11
|
5/12
|
5/15
|
6/15
|
0.32
|
30-day mortality
|
0/50
|
0/34
|
0/11
|
|
0/10
|
0/12
|
0/14
|
0/14
|
|
1 year mortality
|
1/31
|
0/22
|
1/8
|
0.27
|
0/5
|
0/9
|
0/11
|
1/6
|
0.35
|
LOS (days)
|
7 (6-8) (n=52)
|
6.5 (6-7)
|
7 (6-8) (n=14)
|
0.58
|
6 (5-6)
|
6.5 (6-8)
|
7 (5-8)
|
7 (6-7)
|
0.18
|
EBL (mL)
|
300 (n=47)
(150-500)
|
225
(100-388)
|
500
(250-825)
|
0.007
|
250
(100-400)
|
250
(100-675)
|
300
(150-550)
|
350
(200-500)
|
0.71
|
Post-operative blood loss anemia requiring transfusion was the second most common complication, affecting 36% of patients. Active post-operative hemorrhage occurred in 4 patients as UGI bleeding (n = 2) or intraabdominal bleeding (n = 2) requiring re-exploration. Bile leaks occurred in four patients with a leak-to-resected lesion ratio of 0.9%. Two cases resolved spontaneously without added intervention, one case resulted in a biloma requiring percutaneous drainage, and one case occurred after re-exploration for delayed intra-abdominal bleeding and required biliary stenting. GI complications including persistent ileus (n = 2), delayed gastric emptying (n = 1) or post-operative bowel obstruction (n = 1) occurred in 4 patients. Of these, the obstructed patient required re-exploration to rule out bowel ischemia. There was one case of portal vein thrombosis that occurred in the setting of HIT and required anticoagulation. Infectious complications including urinary tract infection (n = 2), pancreatic fistula (n = 3), or intra-abdominal abscess (n = 3) requiring intervention occurred in 8 patients. Overall, 13% of patients had a Clavien-Dindo grade 3 or 4 complication. While there was no 30-day mortality in our patient group, one patient died on POD 38 from NSAID-induced UGI bleeding that was managed outside of our institution.
Post-operatively, median long-term follow-up was 12.1 months (Table 4). All symptomatic patients reported symptom improvement or relief after surgery. Over 80% of patients had a biochemical response with a > 50% decrease in serotonin levels after surgery. 50% of patients did not require subsequent systemic therapy at their most-recent follow-up and either had no evidence of disease (n = 17) or stable disease without progression (n = 9). The median time to recurrence after debulking was 10.9 months for all patients. There was no significant difference in PFS between PNET and SBNET patients (Fig. 3A 11.9 vs. 22.3 months; p = 0.095) or between patients with higher vs. lower number of lesions debulked (Fig. 3B 1–15 lesions: 22.8 months vs. >15 lesions: 16 months; p = 0.38). In cases of disease progression, five patients required the addition of PRRT: 40% had decrease in hepatic lesion size while 60% halted in disease progression. One PNET patient required CAPTEM as subsequent systemic therapy followed by pembrolizumab for tumor de-differentiation. Seven patients underwent post-operative LDT for disease recurrence with either bland embolization or percutaneous ablation. Hazard regression univariate analysis (Table 5) indicated that among our cohort, primary tumor size, higher numbers of hepatic lesions, EHD, and other pathologic variables did not correlate with disease progression.
Table 4. “Postoperative characteristics after tumor debulking by NET type”.
|
All
|
SBNET
|
PNET
|
p
|
Symptomatic response
Biochemical response
Chromogranin
Serotonin
|
24/24
12/19
--
|
21/21
11/17
5/6
|
3/3
1/2
--
|
1.00
1.00
|
Final Pathology
Ki-67
< 3%
3-5%
5-10%
>10%
Lymphovascular invasion
Perineural invasion
Mesenteric deposits
|
25/35
5/35
4/35
1/35
35/36
33/37
20/53
|
21/26
2/26
2/26
1/26
25/26
24/27
20/34
|
4/9
3/9
2/9
0/9
10/10
9/10
0/15
|
0.08
1.00
1.00
<0.001
|
Adjuvant systemic therapy
None
1 agent
2 agents
3 or more agents
|
26/51
17/51
4/51
4/51
|
17/34
12/34
2/34
3/34
|
6/14
5/14
2/14
1/14
|
0.41
|
Liver-directed perc ablation
|
8/43
|
3/29
|
5/11
|
0.01
|
Median time to (months):
Most recent follow-up
Recurrence
1st adjuvant therapy
2nd adjuvant therapy
3rd adjuvant therapy
Liver-directed therapy
|
12.1 (3.9-21.0) (n=52)
10.9 (6.7-18.7) (n=24)
1.6 (0.9-8.3) (n=23)
12.0 (10.3-21.2) (n=7)
14.0, 16.3, & 21.9 (n=3)
14.5 (9.0-20.5) (n=8)
|
15.0 (4.8-22.7) (n=34)
13.6 (7.4-19.4) (n=16)
4.9 (1.5-14.6) (n=15)
16 (10.7-22.6) (n=4)
16.3 and 21.9
(n=2)
10.2, 16.8, & 20.0
(n=3)
|
6.7 (2.4-18.5) (n=15)
9.6 (5.8-15.6) (n=7)
0.8 (0.6-1.0) (n=8)
10.1, 10.4 & 22.4 (n=3)
14.0
(n=1)
12.1 (5.7-21.9) (n=5)
|
0.13
0.41
0.004
0.86
0.67
1.00
|
Table 5. “Univariate analysis of clinicopathologic variables associated with progression free survival.”
|
Hazard Ratio
|
p-value
|
Age >= 65
|
0.69
|
0.55
|
Gender: Male vs. Female
|
1.13
|
0.77
|
Race/Ethnicity
White vs. Black
Hispanic vs. Black
|
1.79
2.33
|
0.67
|
SBNET vs. PNET
|
0.46
|
0.12
|
Synchronous vs. Metachronous
|
1.07
|
0.88
|
Symptomatic disease
|
1.11
|
0.80
|
Tumor grade (2 vs. 1)
|
1.75
|
0.18
|
Bilateral liver metastases
|
2.39
|
0.36
|
Extrahepatic disease
|
2.52
|
0.08
|
# of liver lesions debulked
|
1.01
|
0.53
|
Number of lesions
6-15 vs. 1-5
16-25 vs. 1-5
>25 vs. 1-5
|
2.80
2.91
2.27
|
0.33
|
Primary tumor >= 2cm
|
1.01
|
0.99
|
Largest met >= 5cm
|
0.64
|
0.32
|
Lymphovascular invasion
|
0.89
|
0.92
|
Perineural invasion
|
0.62
|
0.65
|
Mesenteric deposits
|
0.54
|
0.17
|
Ki-67*
3-5% vs. <3%
6-10% vs. <3%
|
1.42
1.08
|
0.91
|
Any preop systemic therapy
Somatostatin analogue
Chemo (CAPTEM)
PRRT
|
7.12
3.58
0.64
1.32
|
0.01
0.04
0.65
0.72
|
Adjuvant (post op) systemic therapy
1 agent vs. 0 agents
2 or more agents vs. 0 agents
SSA
Chemo
PRRT
Ablation (MWA, RFA)
Embolization
Any LDT
|
0.79
4.07
1.40
3.35
3.24
3.28
3.86
3.83
|
0.66
0.01
0.44
0.33
0.04
0.03
0.07
0.01
|
Preop LAD on imaging
|
1.04
|
0.92
|